The mammalian nervous system comprises a peripheral nervous system (PNS) and a central nervous system (CNS, comprising the brain and spinal cord), and is composed of two principal classes of cells: neurons and glial cells. The glial cells fill the spaces between neurons, nourishing them and modulating their function. Certain glial cells, such as Schwann cells in the PNS and oligodendrocytes in the CNS, also provide a myelin sheath that surrounds neural processes. The myelin sheath enables rapid conduction along the neuron. In the peripheral nervous system, axons of multiple neurons may bundle together in order to form a nerve fiber. These, in turn, may be combined into fascicles or bundles.
It has been established that neural stem cells (NSCs) exist in the adult mammalian brain. This fact is of particular importance since the adult brain was thought to have very limited regenerative capacity. New neurons are continuously added to specific regions of the adult mammalian CNS. These neurons are derived from multipotent stem cells that originate from the ependymal layer in the lateral ventricular wall (Johansson et al., Cell 96:25-34 (1999)). Ependymal cells give rise to proliferating cells in the subventricular zone of the ventricle wall, which in turn form neuroblasts. Following migration and differentiation the neuroblasts generate neurons. NSCs also exist in the hippocampal dentate gyrus (Gould et al., Biol. Psychiatry 48:715-720 (2000)). Recently it was demonstrated that the human lateral ventricle and the hippocampus also harbor stem cells capable of generating neurons and glia (Johansson et al., Exp Cell Research 253:733-736 (1999)). The use of adult derived stem cells for tissue repair may help to overcome the ethical problems of embryonic cell research.
The role of stem cells in the adult is to replace cells that are lost by natural cell death, injury or disease. The identifying feature of a stem cell is its ability to exhibit self-renewal or to generate more of itself and, therefore, the simplest definition of a stem cell would be a cell with the capacity for self-maintenance. A more stringent (but still simplistic) definition of a stem cell is provided by Potten and Loeffler (Development, 110:1001, 1990) who have defined stem cells as “undifferentiated cells capable of a) proliferation, b) self-maintenance, c) the production of a large number of differentiated functional progeny, d) regenerating the tissue after injury and e) a flexibility in the use of these options.”
CNS disorders encompass numerous afflictions such as neurodegenerative diseases (e.g. Alzheimer's and Parkinson's), acute brain injury (e.g. stroke, head injury, cerebral palsy) and a large number of CNS dysfunctions (e.g. depression, epilepsy, and schizophrenia). Degeneration in a brain region known as the basal ganglia can lead to diseases with various cognitive and motor symptoms, depending on the exact location. The basal ganglia consists of many separate regions, including the striatum (which consists of the caudate and putamen), the globus pallidus, the substantia nigra, substantia innominate, ventral pallidum, nucleus basalis of Meynert, ventral tegmental area and the subthalamic nucleus. Many motor deficits are a result of neuronal degeneration in the basal ganglia. Huntington's Chorea is associated with the degeneration of neurons in the striatum, which leads to involuntary jerking movements in the host. Degeneration of a small region called the subthalamic nucleus is associated with violent flinging movements of the extremities in a condition called ballismus, while degeneration in the putamen and globus pallidus is associated with a condition of slow writhing movements or athetosis. Other forms of neurological impairment can occur as a result of neural degeneration, such as cerebral palsy, or as a result of CNS trauma, such as stroke and epilepsy.
Another example is Parkinson's disease which is a chronic neurodegenerative disease particularly affecting the neurons of the substantia nigra pars compacta and its nigrostriatal projections. Although Parkinson's disease is considered a multisystem disease, it is mainly a movement disorder caused by a continuous, long lasting degeneration of the dopaminergic neurons that are located in the mesencephalic substantia nigra pars compacta.
Parkinson's disease (PD) is characterized by tremors, hypokinesia, rigidity and abnormal posture as the principal visible symptoms. The tremors in PD are of the resting type, since they occur when the muscles are in a state of relaxation. Its main pathological feature is the degeneration of dopaminergic neurons which have their cell bodies in the substantia nigra and their terminals projecting into the neostriatum. Dopamine is thus significantly depleted in the neostriatum of PD patients. Changes to the substantia nigra and the neostriatal complex are linked to the tremors seen in PD. Compounds that damage the nigrostriatal dopaminergic system and cause hypokinesia, rigidity and tremors have the potential to be used as models for studying PD. Chemical agents such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) damage the nigrostriatal dopaminergic neurons and are widely used to induce symptoms of PD. The effectiveness of these compounds rely on their ability to cause significant damage to the nigrostriatal dopaminergic system. The levels of symptoms are apparently dependent on the degree of nigrostriatal damage, which is somewhat difficult to control. As a result, the symptoms produced by these agents are predominantly rigidity, hypokinesia and movements are not always consistent. Tremor, the most conspicuous symptom of PD is not a characteristic feature of the MPTP and 6-OHDA models.
Levodopa has been historically the medication of choice in treating Parkinson's disease. However, the currently available levodopa preparations are effective only for a relatively short period and may even be deleterious under certain conditions. Administration of levodopa is especially successful during early stages of the disease. Adverse effects of levodopa, such as dyskinesias and hallucinations that occur at early stages of the disease are dose-dependent. These adverse effects are attributed to hypersensitivity of denervated striatal dopaminergic receptors to exogenous dopamine. At late stages of the disease additional types of adverse effects appear as the response to levodopa becomes unpredictable, fluctuative and the duration of the response is reduced.
In order to cure Parkinson's disease, either a grafting procedure of neural tissues to restore dopamine innervation of the stratium or a pharmacological intervention that prevents neural degeneration and triggers renewal of nigral cells must be developed. Recently, transplantation of embryonic dopaminergic neurons have been applied with varying degrees of success (Piccini et al., Ann. Neurol. 48:689-695 (2000); Freed et al., New Engl. J Med. 344:710-719 (2001)). However, while transplantation approaches represent an improvement over currently available treatments, they suffer from a number of significant drawbacks. For example, after transplantation some cell types fail to integrate with host tissue. Another disadvantage is that immunological incompatibility between donor and host could result in the rejection of the implanted cells. There is also the potential that the transplanted cells can result in tumor formation or pass infectious agents from the donor tissue to the host. Another significant drawback of transplantation procedures is that due to the invasiveness of the procedures, which carry the risks involved in any major neurosurgical operation, damage to healthy brain tissue could occur.
Various treatments with hormones (U.S. Pat. No. 5,116,873) and mitogens (U.S. Pat. No. 6,165,783) have been also suggested for restoring the striatal dopamine levels by replenishment of dopamine cells. However, none of the curative treatments have reached the market for larger populations of patients.
Thus, there is a need for improved therapies to treat neurodegenerative diseases. It is also necessary to find therapies for enhancing, improving, repairing, restoring and/or protecting the central nervous system function in a mammal, particularly a human at risk for, or suffering from, a CNS disorder or dysfunction associated with damaged CNS cells. Therefore, this invention fulfills a need in the art for a method for treating central nervous system disease which involves replacing cells lost to the disease.